Gene therapy for Hirschsprung disease?

R. P. Kapur, Masashi Yanagisawa, H. Yanagisawa, J. Rice

Research output: Contribution to journalArticlepeer-review


Congenital intestinal aganglionosis (Hirschsprung disease, HD) affects an estimated 1 in 5000 humans. In patients and murine models, HD has been associated with mutations in genes that encode endothelin receptor B or its ligand, endothelin 3 (et3). et3-mediated signals are necessary for complete colonization of the gut and skin by neural crest cells, which form enteric ganglion cells and cutaneous melanocytes, respectively. The murine kthal spotted (Is) allele is a point mutation in the et3 gene that reduces et3 production to almost undetectable levels in homozygotes. Is/Is mice exhibit intestinal aganglionosis and spotted coat pigmentation. As one means of understanding where and when et3 functions to affect the behavior of enteric and cutaneous neural crest cells, transgenic mice were produced using the human dopamine-β-hydroxlase (DβH) promoter to direct expression of murine et3\o enteric neural precursors and a small subset of other cells in transgenic embryos, but neither melanoblasts nor other cutaneous cells. Two lines of D$H-et3 transgenic mice were produced that expressed moderate and low levels of the transgene. In each case, D$H-et3 transgene had no phenotypic effect on a wild-type or &/+ mice. However, in Is/Is mice, intestinal aganglionosis and spotting were prevented completely by moderate transgene expression and partially by low transgene expression. These results indicate that (1) expression of et3 in enteric neural precursors and a small subset of other embryonic cells is sufficient for normal enteric neurodevelopment, (2) et3 can act via diffusion to prevent spotting in Is/Is embryos, and (3) it may be possible to prevent some forms of HD by genetic or pharmacologie interventions that up-regulate or mimic rf3-mediated signals. (Supported by NIH R01 46277.)

Original languageEnglish (US)
Pages (from-to)516-517
Number of pages2
JournalPediatric Pathology and Laboratory Medicine
Issue number3
StatePublished - 1997

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Pathology and Forensic Medicine


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